Project Summary/Abstract Scandium-44 (44Sc) is a positron emitting radionuclide with a half-life of 3.97 h that is well-suited for use in positron emission tomography (PET) imaging. Scandium-47 (47Sc) is a beta emitter with a half-life of 3.345 d appropriate for targeted radiotherapy. When combined, 44Sc and 47Sc present an ideal radioisotope pair for use in theranostic agents meant to both diagnosis and treat disease. As radiometals, both isotopes of Sc require the use of a bifunctional chelator to attach the radioactive metal cation to a targeting vector that dictates the specific localization of the drug conjugate. Since 44Sc and 47Sc are both up and coming radionuclides for medical applications, there is a need for further chelator development for Sc-based radiopharmaceuticals. The most widely used chelator for Sc(III) is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA); however as a macrocylic chelator, DOTA requires harsh radiolabeling conditions (high temperatures and long reaction times) to form the Sc-DOTA complex that are incompatible with sensitive biological molecules often used as targeting vectors in the drug conjugates. This research aims to investigate and develop an acyclic chelator for stably complexing Sc(III) under biologically compatible radiolabeling conditions to facilitate the use of Sc radioisotopes in targeted radiopharmaceuticals. To achieve these goals, this proposal aims to investigate the chelation chemistry of Sc(III) through the synthesis of small peptides as model systems to probe the effects of denticity, cavity size, and binding moiety on chelate stability, both experimentally and computationally. A series of tripeptides and tetrapeptides comprised of natural and non-natural amino acids will be synthesized and complexed with non-radioactive Sc(III). Selected Sc-peptide complexes will be further studied using density functional theory (DFT) calculations to probe the structure and geometry of the complexes. The trends observed with the peptide systems will inform the selection of promising acyclic chelators to be complexed with non-radioactive Sc and radioactive 44Sc. The acyclic chelators will be assessed based on their ability to readily chelate Sc under mild conditions with high purity, and on complex stability. The lead radiolabeled Sc-chelates will then be evaluated in vivo in mouse models through a collaboration with Memorial Sloan Kettering Cancer Center. PET imaging and biodistribution studies will be carried out to determine the in vivo stability and utility of the acyclic chelators in comparison with the current gold standard DOTA chelator. 44Sc-chelator complexes will be studied in healthy mice while 44Sc-chelator-octreotate (Y3-TATE) bioconjugates will be studied in tumor-bearing mice to monitor targeting to the somatostatin subtype 2 receptor (SSTr2) that are upregulated in neuroendocrine tumors. The development of acyclic chelators for rapid complexation of Sc radionuclides under mild conditions will lead to the development of a novel class of Sc-based radiopharmaceuticals for imaging and treating cancer.